Repurpose Phenformin for the Treatment of NF1-Mutant MPNST
Abstract
Neurofibromatosis type 1 (NF1) is a common disorder (about 1 in 3,000 people) that is caused by genetic mutations in the NF1 tumor suppressor gene. The leading cause of death in individuals with NF1 is the malignant peripheral nerve sheath tumor (MPNST), a highly aggressive soft tissue sarcoma that typically develops from benign plexiform neurofibromas. The lifetime risk of developing MPNST is around 8-13% for NF1 patients, which accounts for about 50% of total MPNSTs. A type of drug called MEK inhibitors (MEKi) has been shown to have limited effect against MPNST when tested in the laboratory. Given this deficit in effective therapies, there is an urgent need to develop better treatment strategies for MPNST, including combining MEKi with other drugs. Phenformin is a drug that was used to treat type 2 diabetes, but was withdrawn in the late 1970s in the United States due to the risk of some side effects in diabetes patients and replaced by a similar drug metformin. Recent animal model studies from our laboratory and others have demonstrated that, compared to metformin, phenformin possesses more potent antitumor activity. Because the toxicity of phenformin is still significantly lower than other commonly used cancer chemotherapies and adjuvant therapies, there is a strong interest in repurposing phenformin for the treatment of cancer. Research from our laboratory has recently demonstrated that phenformin may be useful for treating melanomas that have mutations in NF1. Based on these findings, we plan to evaluate whether combining phenformin with MEKi would have stronger effects against MPNST with NF1 mutations than just MEKi or phenformin by itself when tested in cells and mice in the laboratory. Our proposed studies will not only help to understand why MEKi only has limited effects in MPNST, but also explore a novel treatment strategy for NF1 patients with MPNST. If our hypothesis is proven true, clinical trials could be quickly implemented in 1-2 years to assess the efficacy of phenformin-MEKi combination in NF1 patients with MPNST.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210515
Entities
People
- Bin Zheng
Organizations
- Massachusetts General Hospital
- United States Army